Role of ankyrin-B in human arrhythmia

锚蛋白-B 在人类心律失常中的作用

• 批准号: 8496850
• 负责人: Peter J. Mohler
• 金额: $ 36.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496850
• 关键词: Animal Model; Ankyrins; Antibodies; Arrhythmia; Atrial Fibrillation; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cell membrane; Cells; Charge; Complex; Data; Defect; Developed Countries; Development; Disease; Embryo; Family; Functional disorder; Funding; General Population; Genes; Genetic Variation; Goals; Heart; Heart Atrium; Heart Diseases; Human; Ion Channel; Ions; Learning; Maintenance; Membrane; Membrane Protein Traffic; Membrane Proteins; Molecular; Movement; Mus; Muscle Cells; Pathway interactions; Patients; Phenotype; Physiology; Play; Population; Positioning Attribute; Predisposition; Property; Proteins; Publishing; Regulation; Regulatory Pathway; Research; Role; Signaling Protein; Sinus; Testing; Ventricular; Ventricular Arrhythmia; base; in vivo; innovation; innovative technologies; insight; loss of function mutation; membrane biogenesis; mortality; novel; prevent; programs; sudden cardiac death; therapeutic target; tool; translational study

DESCRIPTION (provided by applicant): Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Ion channels and transporters control the movement of charged ions across cell membranes. In the heart, the coordinate activities of these proteins regulate the transmembrane electrochemical gradient to control depolarization/repolarization, and thus cardiac excitability. Normal function of ion channels and transporters requires defined biophysical properties as well as precise expression, organization, and regulation in defined membrane domains. Findings generated during our first period of funding support a new paradigm for human cardiac disease (arrhythmia) based on dysfunction in proteins that are required for proper expression and local regulation of ion channels and transporters at specific excitable membranes. Specifically, we discovered that ankyrin proteins, previously considered static membrane adapters, play dynamic roles in ion channel, transporter, and signaling protein targeting in ventricular cardiomyocytes. Patients harboring loss-of-function mutations in the ankyrin-B gene (ANK2) display a severe and complex cardiac phenotype. Phenotypes may include sinus node dysfunction, atrial fibrillation (AF), conduction defects, catecholamine-induced polymorphic ventricular arrhythmia, and/or sudden cardiac death. Moreover, we have learned that common ANK2 gene variants in the general population are associated with QTc alterations and ventricular arrhythmia susceptibility, that AnkB levels are strongly altered in large animal models of cardiovascular disease, and that the ANK2 is a candidate gene for AF susceptibility in the general human population. However, despite these translational studies implicating AnkB as a key player in cardiac excitability, the specific molecular roles of AnkB in heart remain surprisingly unknown. In fact, the identities of the in vivo cellular components of the AnkB-targeting pathway (or other cardiac targeting pathways) are still unknown. Finally, lack of an animal model of AnkB deficiency (global AnkB k/o is embryonic lethal) has prevented efforts to define new roles of AnkB in cardiac physiology and disease. For this first competitive renewal, due to important advances during the first funding cycle and the development of a number of innovative new animal models, we are well-positioned to provide the first in vivo information on the fundamental components (both upstream & downstream) of the entire AnkB-targeting pathway at baseline and in disease. We provide exciting new preliminary data that identifies a novel family of membrane trafficking proteins (EHD proteins) that regulate cardiac membrane excitability and associate with AnkB. We further provide new data that AnkB plays a novel role in targeting select Ca2+ channels in sinus node & atria. Finally, our preliminary data in mice demonstrates novel and unexpected roles of AnkB in cardiac membrane biogenesis and maintenance. Together, our published findings and preliminary data support a central hypothesis that the AnkB-based cellular pathway plays dynamic roles in myocyte membrane excitability and cardiac function. The immediate goals of our research program are to understand the specific cellular role(s) of AnkB in the heart (including upstream regulatory pathways [EHD proteins] and novel downstream targets [Cav1.3]) and determine how AnkB dysfunction leads to complex human cardiac disease. For this first competitive renewal, we present a cast of uncharacterized and innovative animal models, novel molecular tools, innovative technologies, and new antibodies to test the specific roles of the AnkB cellular pathway in vivo.

描述(由申请人提供)：心脏兴奋性缺陷是人类心律失常和心脏性猝死的基础，这是发达国家死亡的主要原因。离子通道和转运体控制带电离子在细胞膜上的移动。在心脏中，这些蛋白的协调活动调节跨膜电化学梯度，以控制去极化/复极化，从而控制心脏的兴奋性。离子通道和转运蛋白的正常功能需要明确的生物物理性质，以及在明确的膜结构域上的精确表达、组织和调节。在我们第一期资助期间产生的研究结果支持人类心脏病(心律失常)的新范式，其基础是蛋白质的功能障碍，这些蛋白质是正确表达和局部调节特定可兴奋膜上的离子通道和转运体所必需的。具体地说，我们发现，Ankyrin蛋白，以前被认为是静态的膜适配器，在心室肌细胞中扮演着离子通道、转运蛋白和信号蛋白靶向的动态角色。具有Ankyrin-B基因(ANK2)功能缺失突变的患者表现出严重而复杂的心脏表型。表型可能包括窦房结功能障碍、房颤(AF)、传导缺陷、儿茶酚胺诱导的多形性室性心律失常和/或心脏性猝死。此外，我们还了解到，普通人群中常见的ANK2基因变异与QTC改变和室性心律失常易感性有关，AnkB水平在心血管疾病的大型动物模型中发生强烈变化，ANK2是普通人群房颤易感性的候选基因。然而，尽管这些翻译研究表明AnkB在心脏兴奋性中起关键作用，但令人惊讶的是，AnkB在心脏中的具体分子作用仍然未知。事实上，AnkB靶向通路(或其他心脏靶向通路)的体内细胞成分的身份仍然未知。最后，缺乏AnkB缺乏的动物模型(全球AnkB k/o是胚胎致死的)，阻碍了确定AnkB在心脏生理学和疾病中的新作用的努力。对于这第一次竞争性更新，由于在第一个资金周期中取得的重要进展以及许多创新的新动物模型的开发，我们处于有利地位，能够提供关于整个AnkB靶向通路的基本组成部分(上游和下游)的第一批体内信息。我们提供了令人兴奋的新的初步数据，确定了一个新的膜转运蛋白家族(EHD蛋白)，这些蛋白调节心肌膜的兴奋性，并与AnkB相关。我们进一步提供了新的数据，AnkB在靶向窦房结和心房的选择性钙通道方面发挥了新的作用。最后，我们在小鼠身上的初步数据表明，AnkB在心肌膜生物发生和维持中发挥了新的和意想不到的作用。总之，我们发表的发现和初步数据支持一个中心假设，即基于AnkB的细胞通路在心肌细胞膜兴奋性和心功能中发挥动态作用。我们研究计划的直接目标是了解AnkB在心脏中的特定细胞角色(S)(包括上游调控途径[EHD蛋白]和新的下游靶点[Cav1.3])，并确定AnkB功能障碍如何导致复杂的人类心脏病。对于这第一次竞争性更新，我们提出了一系列未表征的和创新的动物模型、新的分子工具、创新的技术和新的抗体来测试AnkB细胞途径在体内的特定作用。